Loss of muscle mass, or atrophy, is a clinical condition which significantly impacts the rehabilitation medical community. Disuse atrophy and muscle weakness is commonly observed during extended periods of bed rest or cast immobilization, and hampers the rehabilitation of a large proportion of patients with orthopedic injuries. In addition, injuries involving disruption of the normal neural input to muscle such as spinal cord injury are also associated with loss of muscle size and function. The consequences of this loss are far reaching, and include decrease of motor control and overall fitness, development of functional limitations and impairment, and long-term disability. Further, it has become increasingly apparent that loss of muscle mass is associated with an increased risk of secondary complications, such as cardiovascular disease, diabetes and osteoporosis. Therefore, the overall objective of this project is to rescue atrophic muscle and promote motor recover following disuse and spinal cord injury using insulin-like growth factor (IGF-1). IGF-1 has long been recognized as one of the critical factors for coordinating muscle growth, enhancing muscle repair, and increasing muscle mass and strength. It is also a potent motor neuron survival factor. There has been a growing interest in additional active peptides produced by the igf1. Alternative splicing of the gene results in multiple isoforms that retain the same sequence for mature IGF-I, but also give rise to divergent C-terminal sequences, called the E-peptides. Increased levels of these sequences drive unique expression patterns in skeletal muscle, substantiating the identity of novel activities associated with each isoform. Action of the E peptides may be beneficial in circumstances where there is a need for increased muscle mass, repair, and strength. Because IGF-1 (and the E-peptides) could benefit motor neuron survival as well as that of skeletal muscle after injury, we will also determine whether muscle specific expression of IGF-I is sufficient to rescue atrophic muscle and promote recovery in muscle function, or if neuronal expression further facilitates muscle rehabilitation. In addition to independent activity, these peptides may modulate the actions, stability, or bioavailablity of IGF-I. Therefore, the overarching goal of this project is to evaluate the efficacy of IGF-I isoforms and the E peptides in promoting muscle recovery after disuse or spinal cord injury, and to develop new pharmacological agents based on the E peptides. RELEVANCE (See instructions): Loss of muscle mass is a clinical condition which significantly impacts the rehabilitation medical community. The overall objective of this project is to rescue atrophic muscle and promote motor recover following disuse and spinal cord injury using insulin-like growth factor (IGF-1). IGF-1 has been recognized as one of the critical factors for coordinating muscle growth, enhancing muscle repair, and increasing muscle mass and strength.